Use of cilostazol for treatment of sexual dysfunction

ABSTRACT

Methods for treating specific patient groups for sexual dysfunction are provided. The methods of the present invention comprise the utilization of cilostazol and pharmaceutical compositions comprising cilostazol in patients. In one embodiment, patients are free of cardiac disease. In other embodiments, patients have not been treated with a drug that causes hypotensive effects, and/or who have not been given organic nitrites or nitrates. Cilostazol and pharmaceutical compositions of cilostazol are administered to patients orally, cutaneously, transurethrally, intracavemosally, by injection, intranasally, or through respiratory inhalation.

FIELD OF THE INVENTION

The present invention relates to methods for the treatment of sexualdysfunction in males and females (including but not limited to erectiledysfunction in males).

BACKGROUND

Impotence or erectile insufficiency is a widespread disorder that isthought to affect about twelve percent of adult men under ageforty-five, about twenty percent of men at age sixty, and aboutfifty-five percent of men at age seventy-five. Similar to male sexualdysfunction, the prevalence of female sexual dysfunction has been shownto increase with age and be associated with the presence of vascularrisk factors and the development of menopause.

There is more than one cause of erectile dysfunction. For example,erectile dysfunction can be psychological, resulting from anxiety ordepression, with no apparent somatic or organic impairment. Sucherectile dysfunction, which is referred to as “psychogenic”, isresponsible for about fifteen to twenty percent of cases of impotence.In other cases, the erectile dysfunction is associated withatherosclerosis of the arteries supplying blood to the penis; suchdysfunction is referred to as “arteriogenic” or “atherosclerotic.” Aboutforty to sixty percent of cases of impotence are arteriogenic in origin.

In still other cases, there is leakage from veins in the penis such thatsufficient pressure for an erection can be neither obtained normaintained. This dysfunction is referred to as “venous leakage,” or“abnormal drainage”. This condition is often exacerbated by the presenceof some arteriogenic dysfunction whereby the supply of blood to thepenis is impaired. In still other cases, the dysfunction is associatedwith a neuropathy, such as nerve damage arising from, for example,surgery or a pelvic injury, in the nervous system affecting the penis.Such a dysfunction is referred to as “neurogenic” and this accounts forabout ten to fifteen percent of cases of impotence.

There is also a high incidence of erectile insufficiency amongdiabetics, particularly those with insulin-dependent diabetes mellitus.Erectile dysfunction in diabetics is often classified as “diabetogenic,”although the underlying dysfunction is usually neurogenic associatedwith neuropathy, but may be arteriogenic or neurogenic and arteriogenie.About half of diabetic males suffer from erectile insufficiency, andabout half of the cases of neurogenic impotence are in diabetics.

Additionally, erectile insufficiency is sometimes a side effect ofcertain drugs, such as beta-blockers that are administered to reduceblood pressure in persons suffering from hypertension, or drugsadministered to treat depression or anxiety. Excessive alcoholconsumption has also been linked to erectile insufficiency. These formsof erectile insufficiency may be regarded as a subset of neurogenic orpsychogenic insufficiency.

A number of methods to treat impotence are available. These treatmentsinclude pharmacological treatments, surgery and, in cases of psychogenicdysfunction, psychological counseling is sometimes effective.Psychogenic impotence often can be cured by counseling coupled with ademonstration to the patient that he is capable of having a fullerection by inducing such an erection once or a few times in thepatients. Insufficiency due to excessive alcohol consumption issometimes cured by reducing or elimination such consumption.

In rare cases, where the insufficiency is physical because of venousleakage, surgery can usually be employed to repair the venous lesion andthereby either cure the insufficiency or, if there remains an erectileinsufficiency after repair of the venous lesion, render theinsufficiency amenable to treatment by pharmacological methods. Also,penile implants, which provide a mechanical means to produce an erectionsufficient for vaginal penetration, are widely used to treat impotence.In recent years, implants have been employed, especially in cases wherepharmacological intervention is ineffective, which are usually cases ofsevere atherogenic impotence. Treatment of impotence with penileimplants, however, entails serious disadvantages. Such treatmentrequires surgery and necessitates total destruction of the erectiletissues of the penis, forever precluding normal erection.

Pharmacological methods of treatment are also available. Such methods,however, have not proven to be highly satisfactory and can beaccompanied by severe side-effects. Papaverine is now widely used totreat impotence, although papaverine is ineffective in overcomingimpotence due, at least in part, to severe atherosclerosis. Papaverineis effective in cases where the dysfunction is psychogenic or neurogenicand severe atherosclerosis is not involved. Injection of papaverine, asmooth muscle relaxant, or phenoxybenzamine, a non-specific blocker andhypotensive, into a corpus cavernosum has been found to cause anerection sufficient for vaginal penetration. Also, in cases where severeatherosclerosis is not a cause of the dysfunction, intracavernosalinjection of phentolamine, an α-adrenergic blocker, causes an erectionsufficient for vaginal penetration. The resulting erection is one ofsignificantly shorter duration than that induced by intracavernosalinjection of papaverine or phenoxybenzamine and is of such shortduration that satisfactory sexual relations are difficult or impossible.

Treatment of impotence with papaverine or phenoxybenzamine often resultsin priapism, a locking-up of an erection for a long period of time,typically a few hours and sometimes longer than twenty-four hours.Priapism is a serious, deleterious side effect of treatment of erectileinsufficiency with these drugs. Beyond the embarrassment that may becaused for some men, priapism is usually painful, irreversibly damageserectile tissue, and, to be relieved, requires bleeding orpharmacological intervention, such as injection of a sympathomimeticdrug, such as adrenaline.

Even if priapism does not occur with use of papaverine, such use isassociated with a painful, burning sensation in the first two or sominutes after the injection and there are indications that repeated useof papaverine causes undesirable, extensive intracavernous fibrosis.Further, as indicated above, impotence arising from severeatherosclerosis is not susceptible to treatment with papaverine,phenoxybenzamine, phentolamine or papaverine together with phentolamine.In any case, phenoxybenzamine is not suitable for use in treatingimpotence because it is a carcinogen.

Thus, although impotence is a ubiquitous problem, there are fewsatisfactory methods available for treating this disorder. Because ofthe relatively invasive intervention involved and the high failure rateof penile prostheses, surgical approaches provide unattractivealternatives. A safe pharmacological approach to the treatment ofimpotence is still to be achieved.

What is needed is a pharmaceutical that is effective but lacking insignificant side effects.

SUMMARY OF THE INVENTION

The present invention relates to methods for the treatment of sexualdysfunction in males and females (including but not limited to erectiledysfunction in males). While the present invention is not limited totreatment of a particular patient group, it is contemplated that themethods of the present invention comprise the utilization ofpharmaceutical compounds and compositions to patients who are free ofsymptoms of cardiac disease and who have not been treated with drugswhich cause hypotensive effects, such as nitrites and nitrates. Thecompositions comprise quinolines, including derivatives and metabolitesthereof.

It is not intended that the present invention be limited by the natureof the derivative. In a preferred embodiment, the quinoline is anoxoquinoline. In yet another preferred embodiment, the oxoquinoline iscilostazol(6-[4-(1-cyclohexyl-1-H-tetrazol-5-yl)butoxyl]-3,4-dihydro-2(1H)-quinolinone;6-[4-(1-cyclohexyl- 1-H-tetrazol-5-yl)butoxy]-3,4-dihydrocarbostyril;6-[4-(1-cyclohexyl-5-tetrazoyl)butoxy]-1,2,3,4-tetrahydro-2-oxoquinoline).

In yet other preferred embodiments, metabolites of cilostazol arecontemplated for use in the methods of the presently claimed invention.Metabolites of cilostazol include, but are not limited tomonohydroxycilostazol, monohydroxydehydrocilostazol,3,4-dihydro-6-hydroxy-2(1H)-quinolinone, their conjugates anddehydrocilostazol.

In one embodiment, the method comprises a) providing: i) a patient(whether male or female) suffering from symptoms of sexual dysfunction;and ii) cilostazol; and b) administering cilostazol to the patient suchthat such symptoms are reduced. It is not intended that the presentinvention be limited to the mode of administration. In one embodiment,cilostazol is administered orally. In another embodiment, cilostazol isadministered cutaneously. In yet another embodiment, cilostazol isadministered intranasally. In an alternative embodiment, cilostazol isadministered through respiratory inhalation. In yet another alternativeembodiment, cilostazol is administered by standard injection.

In one embodiment, cilostazol is administered as a tablet. In anotherembodiment, cilostazol is administered as a pharmaceutical composition.In yet another embodiment, cilostazol is administered as a single dosageof 100 milligrams per day.

It is not intended that the present invention be limited to thetreatment of certain patient groups. In one embodiment, the patient ismale. In another embodiment, the patient is female. In one embodiment,the patient is free from cardiac disease. In another embodiment, thepatient has not been treated with a drug that causes hypotensiveeffects. In yet another embodiment, the patient has not been treatedwith nitrates or nitrites.

In another embodiment, the method comprises providing: i) a male witherectile dysfunction, and ii) a pharmaceutical composition comprisingcilostazol; and introducing the pharmaceutical composition to the malesuch that an erection is produced.

It is not intended that the present invention be limited by the methodof introduction of cilostazol. In one embodiment, the cilostazol isintroduced into the male orally. In a preferred embodiment, the male isan adult human and the oral dosage is in a single dose per day of 100milligrams.

The present invention is not limited by the degree of response by themale subject. In one embodiment, the erection induced is sufficient forvaginal penetration.

Likewise, the present invention also contemplates the use of sexualstimulation in addition to the application of a pharmaceuticalcomposition. For example, one embodiment comprises a) providing: i) amale, having a penis, with erectile dysfunction, ii) cilostazol, andiii) sexual stimulation; and b) introducing said cilostazol and sexualstimulation to the male such that an erection is produced. In anotherembodiment, the method comprises a) providing: i) a male, having apenis, with erectile dysfunction, ii) a pharmaceutical compositioncomprising cilostazol, and iii) sexual stimulation; and b) introducingsaid cilostazol and sexual stimulation to the male such that an erectionis produced.

Likewise, the present invention is not limited by the nature of thesexual stimulation. In one embodiment, the sexual stimulation issexually explicit media. In another embodiment, the sexual stimulationinvolves manipulation of the penis, such as with vibration.

It is not intended that the present invention be limited by the natureof the formulation. In one embodiment, the present inventioncontemplates a formulation comprising a quinoline or derivative thereofin a mixture comprising lactose.

DEFINITIONS

As used herein, the term “quinoline” refers to chemical compositionscomprising quinoline as set forth in the following structure:

as well as other forms of quinoline (e.g., 2-oxoquinoline):

As used herein, “cilostazol” refers to a chemical compound as set forthin the following structure:

As used herein, a patient who is “free from cardiac disease” and apatient who is “free from symptoms of cardiac disease” indicate that thepatient has not been diagnosed with angina, myocardial infarction,congestive heart failure and that symptoms of angina, ischemia,myocardial infarction, congestive heart failure have not been detected,respectively.

As used herein, “drugs that have hypotensive effects” are those drugswhich, when administered, cause the patient's end-diastolic bloodpressure to be reduced. Nitrates are commonly used drugs which havehypotensive effects.

As used herein, “nitrates” are compounds that contain the —NO₃—moiety.Nitrates typically used in the clinic are shown in Table 1.

As used herein, “nitrites” are compounds that contain the —NO₂—moiety.Nitrites typically used in the clinic are shown in Table 1.

As used herein, the term “erectile dysfunction” refers to certaindisorders of the cavernous tissue of the penis and the associated faciawhich produce impotence, the inability to attain a sexually functionalerection.

As used herein “standard injection” refers to the placement of apharmaceutical composition into a subject (e.g., with a hypodermicneedle). For example, such injection can be made subcutaneously,intravenously, intramuscularly, intracavernosally, etc.

TABLE 1 Organic Nitrates Available for Clinical Use NONPROPRIETARY NAMESAND TRADE CHEMICAL PREPARATIONS, USUAL DOSES, AND NAMES STRUCTURE ROUTESOF ADMINISTRATION* Amyl nitrite (isoamyl nitrite)

Inh: 0.18 or 0.3 ml, inhalation Nitroglycerin (glycerol trinitrate;NITRO-BID, NITROSTAT, NITROL, NITRO-DUR, others)

T: 0.15 to 0.6 mg as needed S: 0.4 mg per spray as needed C: 2.5 to 9 mgtwo to four times daily B: 1 mg every 3 to 5 h O: 1.25 to 5 cm (½ to 2in.), topically to skin every 4 to 8 h # D: 1 disc (2.5 to 15 mg) every24 h IV: 5 μg/min; increments of 5 μg/min Isosorbide dinitrate (ISORDIL,SORBITRATE, DILATRATE, others)

T: 2.5 to 10 mg every 2 to 3 h T(C): 5 to 10 mg every 2 to 3 h T(O): 10to 40 mg every 6 h C: 40 to 80 mg every 8 to 12 hIsosorbide-5-mononitrate (IMDUR, ISMO, others)

T: 10 to 40 mg twice daily C: 60 mg daily Erythrityl tetranitrate(CARDILATE)

T: 5 to 10 mg as needed T(O): 10 mg three times daily *B, buccal(transmucosal) tablet; C, sustained-release capsule or tablet; D,transdermal disc; Inh, inhalant; IV, intravenous injection; O, ointment;S, lingual spray; T, tablet for sublingual use; T(C), chewable tablet;T(O), oral tablet or capsule.

As used herein, “intracavernosal” injection is injection into the corpuscavernosum of the penis.

As used herein, an “erection” refers to the condition of a penis wherebyit is at least semi-rigid as opposed to being in a flaccid state.

As used herein, “by oral administration” refers to the introduction of apharmaceutical composition into a subject by way of the oral cavity(e.g., in aqueous liquid or solid form).

As used herein, “cutaneously” refers to the introduction of apharmaceutical composition into a subject by application to the surfaceof the skin such that the composition is absorbed into the subject.

As used herein, “transurethrally” refers to the introduction of apharmaceutical composition to the urethra of a subject such that thecomposition is absorbed into the subject.

As used herein, “intranasally” refers to the introduction of apharmaceutical composition within the nasal cavity.

As used herein, “respiratory inhalation” refers to the introduction of apharmaceutical composition within the respiratory tract.

As used herein, “sufficient for vaginal penetration” refers to the stateof an erection such that the penis is capable of entering a vaginawithout manual manipulation.

As used herein, “sexual stimulation” refers to activity that wouldinduce an erection in a male without erectile dysfunction (e.g.,sexually explicit media, manual manipulation, vibration, live eroticentertainment, etc.)

As used herein, “sexually explicit media” refers to films, videos,books, magazines, etc. that depict sexual activity.

As used herein “single dosage” refers to a pharmaceutical composition ofa formulation that is capable of achieving its intended effect in asingle application.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to methods for the treatment of sexualdysfunction in males and females (including but not limited to erectiledysfunction in males). The compositions comprise quinolines, includingderivatives thereof.

In one embodiment, the present invention contemplates the use ofcompositions that are effective to induce an erection in a human malesuffering from impotence of any origin, other than anatomicaldeficiencies (i.e., lacking a penis or a significant portion thereof)that preclude an erection sufficient for vaginal penetration. Inparticular, these compositions may be used to induce an erection in amale suffering from impotence caused by severe atherosclerosis, and alsoimpotence that is neurogenic or psychogenic in origin. The compositionsutilized in the methods of the present invention comprise cilostazol,including derivatives thereof.

Cilostazol is a phosphodiesterase inhibitor (type III) that suppressesplatelet aggregation and also acts as a direct arterial vasodilator. Inaddition to its reported vasodilator and antiplatelet effects,cilostazol has been proposed to have beneficial effects on plasmalipoproteins, increasing plasma high density lipoprotein cholesterol andapoliproprotein (See e.g., Dawson et al., Circulation 98: 678-686[1998]; Elam et al., Arterioscler Thromb. Vasc. Biol. 18:1942-1947[1998]; Drug Evaluation Monographs, vol. 99, Micromedex Inc.).

Method of preparation of cilostazol are set forth by Nishi et al. (Chem.Pharm. Bull. 31: 1151[1983], and U.S. Pat. No. 4,277,479, herebyincorporated by reference), and its pharmacology, metabolism, mechanismof action and clinical evaluations are described in Arzneimittel-Forsch.35: 1117-1208 (1985), hereby incorporated by reference. While it is notnecessary to understand any particular mechanism to carry out thepresent invention, it is believed that in some circumstances cilostazolcan act as a direct-acting vasodilator to relax the corpus cavernosumsmooth muscle cells, which in turn increases blood flow into thecavernosa space. This then leads to increased cavernosa pressure toproduce an erect penis.

In one embodiment cilostazol is administered. It is contemplated thatcilostazol be administered cutaneously, transurethrally, by standardinjection, intracavernosally, intranasally or through respiratoryinhalation, although it is not intended that the methods of the presentinvention be limited to the mode of administration of cilostazol. In oneembodiment, cilostazol is administered as a tablet. In anotherembodiment, cilostazol is administered as a pharmaceutical composition.

While the present invention is not limited to the treatment of aparticular patient group, it is contemplated that the methods of thepresent invention comprise the utilization of pharmaceutical compoundsand compositions to patients who are free of symptoms of cardiac diseaseand who have not been treated with drugs which cause hypotensiveeffects, such as nitrites and nitrates. In some embodiments, cilostazolmay potentiate the hypotensive effects of nitrates, and itsadministration to patients who are concurrently using organic nitratesin any form may be contraindicated.

DIAGNOSIS OF MALE ERECTILE DYSFUNCTION

Determination whether a human male is suffering from impotence that issubstantially only neurogenic or psychogenic is readily made by a personskilled in the art using a number of readily available diagnosticprocedures. Thus, a male suffering from impotence can first be given aphysical examination with particular attention to possible penile andscrotal pathology, whereby any anatomical deficiency precluding anerection sufficient for vaginal penetration can be detected. In theabsence of such an anatomical deficiency, the male can be subjected totests, whereby penile venous leakage or severe or untreatableatherosclerosis can be detected.

Such tests include determination of the penobrachial blood pressureindex (PBPI), doppler investigation of the penile arteries, and apapaverine test. The PBPI is the penile systolic blood pressure dividedby the systolic blood pressure determined at one of the arms. Theseblood pressures can be determined by any number of standard techniques.Thus, the penile systolic blood pressure can be determined by i) placingan inflatable cuff around the base of the free part of the penis in theflaccid state which is capable of being used to apply variable pressure,readable from a gauge, to an object around which the cuff is placed, ii)localizing the penile arteries with a Doppler ultrasound probe (e.g., 8MHz probe, such as the Mini Doplex D500 available from HuntleighTechnology, Luton, United Kingdom), and then iii) inflating anddeflating the cuff and ascertaining the pressure at which the Dopplersound reappears.

The pressure at which the Doppler sound reappears is the penile systolicblood pressure. A male's penile blood pressure is regarded as normal ifhis PBPI is >0.80. With regard to Doppler investigation, each of the twopenile cavernous arteries is investigated distal to the aforementionedcuff using the Doppler ultrasound problem. The function of each of thetwo arteries is assessed by Doppler ultrasound using an arbitrary scaleof 0, 1, 2 or 3, where 0 means that the function is so deficient thatthe artery cannot be located and 3 means that the artery is well enoughthat maximal Doppler sound is observed.

In the papaverine test, a tourniquet is placed at the base of the freepart of the penis and tightened and then, with the patient seated, 30 mgof papaverine in 1 ml of a physiologically acceptable fluid (e.g.,physiological saline or phosphate-buffered saline) is injected into thepenile cavernous body. In persons suspected of having impotence due to asuprasacral nerve lesion or a psychogenic dysfunction, only 15 mg ofpapaverine is administered, because of the high incidence ofpapaverine-induced priapism in such cases.

Five minutes after the injection, the tourniquet is removed and anultrasound Doppler investigation of the penile cavernous arteries iscarried out as described above. The function of the arteries is regardedas normal if both of them score a 3 on the arbitrary scale. After theDoppler investigation, penile vibration, at about a 4 Hz with anamplitude of about 1.2 mm (carried out with, e.g., a Vibrector, fromMulticept, Gentofte, Denmark) is carried out for five to ten minutes andthen erectile response is evaluated.

Erectile response is classified as full rigidity, if the angle betweenthe penis and the legs in the standing position is >90°, and tumescenceor no response if the angle is less than or equal to 45°. An impotentmale, who does not have an anatomical deficiency that would precludehaving an erection sufficient for vaginal penetration, who has aPBPI >0.80, who has scores of 2 or 3 in Doppler ultrasoundinvestigations of both of the cavernous arteries of the penis, afterpapaverine injection as described above, and who has a fully rigiderection after papaverine injection and vibration as described above, issuffering from impotence that is “substantially only neurogenic orpsychogenic” in origin.

It is possible that atherosclerosis or venous leakage contributes tosuch impotence, and atherosclerosis likely does contribute if the scoreis less than 3 in the Doppler investigation of one or both of thecavernous arteries after papaverine injection; but any venous leakage oratherosclerosis in such impotence is not untreatable and, consequently,is not a substantial factor in the impotence and such atherosclerosis,if any, is less than severe.

Impotence, which is a side-effect of drugs such as beta-blockers, isdeemed to be neurogenic impotence in the present specification.Similarly, impotence which is a result of alcoholism or excessiveconsumption of alcohol, is deemed to be neurogenic or psychogenicimpotence, for purposes of the present specification. Thus, a male whois diagnosed in accordance with the present specification as sufferingfrom impotence that is “substantially only neurogenic or psychogenic” inorigin is suffering from impotence that is substantially onlyneurogenic, psychogenic or neurogenic and psychogenic in origin, eventhough an underlying cause of the impotence has been identified as aside-effect of a drug, alcoholism or excessive consumption of alcohol.

Generally, a male with a PBPI less than about 0.60, with scores of 0 inDoppler investigations of both penile cavernous arteries (afterpapaverine injection as described above), and with a less than fullyrigid erection after papaverine injection and vibration will haveimpotence caused by “untreatable” atherosclerosis. Methods are availableto ascertain whether impotence is untreatable because of venous leakage.

One method of ascertaining whether untreatable venous leakage is a causeof impotence is by cavemosometry, optionally supplemented withcavernosography. [See, e.g., Delcour et al., Radiology 161:799 (1986);Porst et al., J Urol. 137:1163 (1987); Lue et al., J. Urol. 37:829(1987)]. Cavernosometry can be done using, both before and afterintracavernosal injection of 60 mg of papaverine (in 1 ml ofphysiological saline), infusion of physiological saline through a19-gauge needle into one corpus cavernosum with a 21-gauge needleinserted into the other corpus cavernosum for measurement ofintracorporal pressure (which is recorded on a plotter).

The infusion rates needed to induce and maintain an erection aremeasured. If the infusion rate needed to maintain an erection is greaterthan 50 ml/min before administration of the papaverine and greater than15 ml/min after administration of the papaverine, untreatable venousleakage is present. As long as an erection can be achieved at some flowrate less than about 100 ml/min before injection of the papaverine andless than about 50 ml/min after the injection of papaverine, it might bepossible, using cavernosography, to locate the venous lesion associatedwith the leakage, and thereby confirm the diagnosis based oncavernosometry and provide information for possible surgical correctionfor the leakage. In the cavernosography, the penis is X-rayed, bothbefore and after intracavernosal injection of 60 mg papaverine (in 1 mlof physiological saline), while infusing contrast medium into the corpuscavernosum (e.g., through a 19-gauge needle) at a flow rate thatmaintains an erection during the X-ray. Numerous contrast media suitablefor the procedure are available in the art; these are typically aqueoussolutions of iodinated compounds that provide between about 180 mg/mland about 360 mg/ml of iodine. Examples are a solution of iohexolproviding 240 mg/ml of iodine sold by Winthrop Pharmaceuticals, NewYork, N.Y., USA, and a solution of iopamidol providing 300 mg/ml iodinesold by Astra Meditec, Goteborg, Sweden. Typically 50-100 ml of thecontrast medium will be employed for each x-ray (i.e., before and thenafter the injection of papaverine). In the cavernosometry andcavernosography, 30 mg papaverine (in 1 ml physiological saline) coupledwith stimulation by vibration can be employed in place of 60 mgpapaverine (in 1 ml physiological saline).

TREATMENT OF MALE ERECTILE DYSFUNCTION

It is not intended that the present invention be limited by theparticular nature of the therapeutic preparation. For example,cilostazol can be provided together with physiologically tolerableliquid, gel or solid carriers, diluents, adjuvants and excipients. Inaddition, cilostazol formulations may also contain such normallyemployed additives as binders, fillers, carriers, preservatives,stabilizing agents, emulsifiers, buffers and excipients as, for example,pharmaceutical grades of mannitol, lactose, starch, magnesium stearate,sodium saccharin, cellulose, magnesium carbonate, and the like.

The present invention is not limited by the method of introduction ofthe therapeutic compound to the body. Among other methods, the presentinvention contemplates administering cutaneously, orally,intracavemosally, transurethrally, by standard injection, intranasallyor through respiratory inhalation.

While the present invention is not limited to a specific dosage level, asingle dosage per day of 100 milligrams for adult humans iscontemplated. Multiple dosage is also contemplated. In anotherembodiment, a dosage of less than 100 milligrams per day is contemplated(i.e., 50 to 75 milligrams).

Peak plasma concentrations of cilostazol are observed 2-4 hoursfollowing oral administration (See e.g., Suri et al., J. Clin.Pharmacol. 38: 144-150 [1998]; Niki and Mori, Arzneimittelforschung 35:1173-1185 [1985]).

While the present invention is not limited by the form of oraladministration, aqueous and organic solutions of cilostazol for oraladministration are contemplated. Likewise, cilostazol can be associatedwith a solid pharmaceutical carrier for solid oral administration. Thecompositions may be formulated in a manner known to one skilled in theart, using pharmaceutically acceptable carriers suitable for use in suchcompositions that are also well known in the art. It is contemplatedthat the compositions of the present invention comprise 0.1-90% byweight of cilostazol. In one embodiment, cilostazol can be prepared intablet form by mixing cilostazol with an inert diluent such as lactose(See e.g., U.S. Pat. No. 5,627,191 to Birch et al., hereby incorporatedby reference). In one preferred embodiment, cilostazol is administeredas a tablet.

Cilostazol may also be administered cutaneously in a carrier adapted fortopical administration. Such carriers include creams, ointments,lotions, pastes, jellies, sprays, aerosols, bath oils, or otherpharmaceutical carriers which accomplish direct contact betweencilostazol and the pore of the skin. In some cases it may be necessaryto dissolve cilostazol in an appropriate organic solvent to facilitateincorporation into a pharmaceutical preparation. One skilled in the artis able to readily prepare such pharmaceutical formulations (See e.g.,U.S. Pat. No. 5,719,197 to Kanios et al., hereby incorporated byreference).

Likewise, the present invention can be incorporated in other productsassociated with sexual activity. For example, a coated, erectioninducing condom as disclosed in U.S. Pat. No. 4,829,991, herebyincorporated by reference, can be utilized with cilostazol.

While the present invention is not limited by a specific method ofintroducing cilostazol intracavemosally, injection of cilostazol can becarried out by any conventional injection means (e.g., employing anhypodermic syringe and needle or a similar device such as theNovolinPen. sold by Squibb-Novo, Inc., Princeton, N.J., USA). Thisinjection may be by subject injecting himself or by another person (suchas a partner during sexual relations or a physician prior to sexualrelations) injecting the male whose erection is to be induced. Methodsfor intracavemosal injection are described in U.S. Pat. No. 5,447,912 toGerstenberg et al., hereby incorporated by reference.

Cilostazol can be introduced intracavemosally in a physiologicallyacceptable composition. Such compositions are aqueous solutions that arephysiologically acceptable for administration by intracavemosalinjection into the penis. The physiologically acceptable carrier isselected such that it is not painful or irritating upon intracavernosalinjection. The physiologically acceptable compositions will preferablybe sterile at the time of administration by intracavernosal injection.

Among the physiologically acceptable compositions for use in the methodsis physiological saline or phosphate buffered saline, in whichcilostazol is dissolved or suspended, such that the resultingcomposition is suitable for intracavernosal injection.

In carrying out the methods, it is preferred that, for a period of timebetween about 1 minute and about 15 minutes (preferably about 5minutes-10 minutes), the penis is constricted near the base thereof andbetween the base and the point at which the injection into a corpuscavernosum occurs, in order to limit loss of injected fluid from thecorpus cavernosum before the ingredients in the fluid, that are activein inducing erection, have been able to have erection-inducing effects.The constriction can be effected by any means known in the art, such aswith a tourniquet, cuff, rubber band or the like, or even manually, inorder to slow the release of the injected fluid and thepharmacologically active substance(s) therein into the generalcirculation.

Likewise, the present invention is not limited by a particular methodfor introducing cilostazol transurethrally. In one embodiment,cilostazol is introduced to the urethra in a carrier as described forcutaneous administration. Devices and methods for transurethralintroduction of pharmaceutical compositions is described in U.S. Pat.No. 5,474,535 to Place et al.; Voss, U.S. Pat. No. 4,801,587 and Kock,EPA 0357581, all hereby incorporated by reference.

Additional methods of introducing cilostazol transurethrally include theuse of medicated catheters, such as those used to prevent or treatlocalized infections and irritation of the urethra and bladder (See U.S.Pat. No. 4,640,912, hereby incorporated by reference). Alternatively,transurethral administration of pharmaceutical compositions is presentedin U.S. Pat. Nos. 4,478,822, 4,610,868, 4,640,912 and 4,746,508, allhereby incorporated by reference, and medicated urethral suppositories,inserts or plugs, typically containing anti-infective agents orspermicide are disclosed in U.S. Pat. Nos. 1,897,423, 2,584,166,2,696,209 and 3,373,746, all incorporated by reference.

While the present invention is not limited to the method of injectingcilostazol in the preferred embodiment, cilostazol is injected with astandard syringe. One skilled in the art would be capable of injectingcilostazol with a carrier as described for intracavernosal injection.

Cilostazol may also be administered intranasally. Formulations suitablefor intranasal administration include ointments, creams, lotions,pastes, gels, sprays, aerosols, oils and other pharmaceutical carrierswhich accomplish direct contact between cilostazol and the nasal cavity.Examples of pharmaceutical compositions administered intranasally aredescribed in U.S. Pat. Nos. 5,393,773 and 5,554,639 to Craig et al.;5,603,943 to Yanagawa; and 5,801,161 to Merkus, all hereby incorporatedby reference.

Cilostazol may also be administered through respiratory inhalation.Formulations suitable for respiratory inhalation include ointments,creams, lotions, pastes, gels, sprays, aerosols, oils and otherpharmaceutical carriers which accomplish direct contact betweencilostazol and the respiratory tract. Examples of pharmaceuticalcompositions administered through respiratory inhalation are describedin U.S. Pat. Nos. 4,552,891 to Hu et al.; 5,869,479 to Kreutner et al.,and 5,864,037 to Chasis et al.

In some embodiments, intranasal administration and respiratoryinhalation are the preferred modes of administration due to the ease ofadministration and faster onset of therapeutic activity. It iscontemplated that intranasal administration and respiratory inhalationare advantageous as they may allow a smaller effective dosage to beadministered than would be possible with the oral route ofadministration. A preferred mode of administration comprisesadministration to the lung. Intrapulmonary delivery of pharmacologicagents to patients can be accomplished via aerosolization.Alternatively, the agent may be administered to the lung through abronchoscope. Of course, the therapeutic agents may be investigated fortheir efficacy via other routes of administration, including parenteraladministration.

In one embodiment, the administration of the compositions of the presentinvention is accompanied by sexual stimulation to induce an erection.The sexual stimulation can begin before or after the introduction ofcilostazol. If the stimulation begins after the injection, it ispreferably begun within 5 to 10 minutes to insure that there issignificant overlap of the pharmacological effects of the pharmaceuticalcomposition administered and the stimulative effects of the sexualstimulation. Whether the stimulation begins before or after theinjection, it will continue preferably at least until an erectionsufficient for vaginal penetration is achieved.

Sexual stimulation as prescribed by these methods, includes any form ofsexual stimulation that would induce an erection in a normal male who isnot suffering from erectile insufficiency. The sexual stimulation can bethat which occurs in the course of sexual relations between the subjectand another person or can be outside sexual relations with anotherperson. Examples of methods of sexual stimulation include, alone or incombination, touching or erotically manipulating erogenous areas of thegenital organs or other erogenous parts of the body; providing visualstimulation, as with a sexually explicit media (e.g., pornographic film)or other form of sexually stimulative show or display. Additionally,providing vibratory stimulation to the penis, at between about 30 Hz andabout 100 Hz with an amplitude of about 1 mm to about 5 ram, as can beprovided, for example, by resting the penis on the table of a vibratingapparatus such as that of a Vibrector system (Multicept, Genofte,Denmark).

In inducing an erection in an impotent male outside of sexual relations,as, for example, when a physician induces an erection in a patientsuffering from psychogenic impotence, a preferred method of sexualstimulation includes providing visual stimulation, as with apornographic film, simultaneously with vibratory stimulation of thepenis, as with a Vibrector system set to between about 30 Hz and about60 Hz (usually about 50 Hz)in frequency and between about 1 mm and about2.5 mm (usually about 2.2 mm) in amplitude.

From the above, it should be clear that the present invention providesmethods of treatment of male erectile dysfunction with pharmaceuticalagents. In particular, cilostazol is administered therapeutically topatients having such dysfunction.

All publications and patents mentioned in the above specification areherein incorporated by reference. Various modifications and variationsof the described method and system of the invention will be apparent tothose skilled in the art without departing from the scope and spirit ofthe invention. Although the invention has been described in connectionwith specific preferred embodiments, it should be understood that theinvention as claimed should not be unduly limited to such specificembodiments. Indeed, various modifications of the described modes forcarrying out the invention which are obvious to those skilled in the artare intended to be within the scope of the following claims.

I claim:
 1. A method, comprising: a) providing: i) a patient sufferingfrom symptoms of sexual dysfunction, and ii) cilostazol; and b)administering said cilostazol to said patient such that such symptomsare reduced.
 2. The method of claim 1, wherein said administering stepis orally.
 3. The method of claim 1, wherein said administering step iscutaneously.
 4. The method of claim 1, wherein said administering stepis intranasally.
 5. The method of claim 1, wherein said administeringstep is through respiratory inhalation.
 6. The method of claim 1,wherein said administering step is by injection.
 7. The method of claim1, wherein said cilostazol is administered as a pharmaceuticalcomposition.
 8. The method of claim 1, wherein said cilostazol isadministered as a single dosage of 100 milligrams per day.
 9. The methodof claim 1, wherein said cilostazol is administered as a tablet.
 10. Themethod of claim 1, wherein said patient is male.
 11. The method of claim1, wherein said patient is female.
 12. The method of claim 1, whereinsaid patient is free of cardiac disease.
 13. The method of claim 1,wherein said patient is not being treated with a drug that causeshypotensive effects.
 14. The method of claim 1, wherein said patient isnot being treated with nitrates or nitrites.
 15. A method, comprising:a) providing: i) a patient suffering from symptoms of sexualdysfunction, wherein said patient is not being treated with nitrates andii) cilostazol; and b) administering said cilostazol to said patientsuch that said symptoms are reduced.
 16. The method of claim 15, whereinsaid administering step is by injection.
 17. The method of claim 15,wherein said administering step is by oral administration.